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EP4559565A1 - Procédé de revêtement d'un non-tissé de fibres de verre, filtre à fibres de verre revêtu et ses utilisations - Google Patents

Procédé de revêtement d'un non-tissé de fibres de verre, filtre à fibres de verre revêtu et ses utilisations Download PDF

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Publication number
EP4559565A1
EP4559565A1 EP23212012.1A EP23212012A EP4559565A1 EP 4559565 A1 EP4559565 A1 EP 4559565A1 EP 23212012 A EP23212012 A EP 23212012A EP 4559565 A1 EP4559565 A1 EP 4559565A1
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EP
European Patent Office
Prior art keywords
glass fiber
copolymer
fiber fleece
typically
acrylamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP23212012.1A
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German (de)
English (en)
Inventor
Eloisa Lopez-Calle
Moritz Marcinowski
Jürgen Spinke
Thomas Brandstetter
Holger Frey
Nicolas Geid
Jürgen Rühe
Frank SCHERAG
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Roche Diagnostics GmbH
Albert Ludwigs Universitaet Freiburg
Original Assignee
F Hoffmann La Roche AG
Roche Diagnostics GmbH
Albert Ludwigs Universitaet Freiburg
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG, Roche Diagnostics GmbH, Albert Ludwigs Universitaet Freiburg filed Critical F Hoffmann La Roche AG
Priority to EP23212012.1A priority Critical patent/EP4559565A1/fr
Priority to PCT/EP2024/083324 priority patent/WO2025109187A1/fr
Publication of EP4559565A1 publication Critical patent/EP4559565A1/fr
Withdrawn legal-status Critical Current

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/10—Supported membranes; Membrane supports
    • B01D69/106—Membranes in the pores of a support, e.g. polymerized in the pores or voids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D39/00—Filtering material for liquid or gaseous fluids
    • B01D39/14—Other self-supporting filtering material ; Other filtering material
    • B01D39/20—Other self-supporting filtering material ; Other filtering material of inorganic material, e.g. asbestos paper, metallic filtering material of non-woven wires
    • B01D39/2003—Glass or glassy material
    • B01D39/2017—Glass or glassy material the material being filamentary or fibrous
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
    • B01D67/0081—After-treatment of organic or inorganic membranes
    • B01D67/0088—Physical treatment with compounds, e.g. swelling, coating or impregnation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/10—Supported membranes; Membrane supports
    • B01D69/108—Inorganic support material
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/40—Polymers of unsaturated acids or derivatives thereof, e.g. salts, amides, imides, nitriles, anhydrides, esters
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/40—Polymers of unsaturated acids or derivatives thereof, e.g. salts, amides, imides, nitriles, anhydrides, esters
    • B01D71/401—Polymers based on the polymerisation of acrylic acid, e.g. polyacrylate
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/76—Macromolecular material not specifically provided for in a single one of groups B01D71/08 - B01D71/74
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood
    • G01N33/491—Blood by separating the blood components
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2239/00—Aspects relating to filtering material for liquid or gaseous fluids
    • B01D2239/04—Additives and treatments of the filtering material
    • B01D2239/0414—Surface modifiers, e.g. comprising ion exchange groups
    • B01D2239/0421—Rendering the filter material hydrophilic
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2239/00—Aspects relating to filtering material for liquid or gaseous fluids
    • B01D2239/04—Additives and treatments of the filtering material
    • B01D2239/0471—Surface coating material
    • B01D2239/0492—Surface coating material on fibres
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2323/00—Details relating to membrane preparation
    • B01D2323/02—Hydrophilization
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2323/00—Details relating to membrane preparation
    • B01D2323/30—Cross-linking

Definitions

  • the present invention relates to a method for coating a glass fiber fleece comprising contacting the surface of a glass fiber fleece with a hydrophilic copolymer; and crosslinking the copolymer.
  • the invention further relates to a glass fiber filter, comprising a glass fiber fleece, wherein the surface of the glass fiber fleece is coated with a hydrophilic copolymer; and to a device for biomedical filter applications comprising the same.
  • the filtering process or material should not cause hemolysis, i.e., rupture of the blood cells during separation; otherwise, cellular fragments could interfere with accurate downstream measurements. Further, denaturing and/or unspecific binding of the components of the blood plasma or serum, such as proteins and lipids, should be avoided during the separation process. For rapid diagnostic applications, as in Point of Care (POC) applications, minimizing the time and the space required for the separation is also desirable.
  • POC Point of Care
  • test elements In a (POC) environment, usually, small test elements, or test strips, are used containing dried reagents capable of performing an analytical assay, in particular an immunoassay, when redissolved by a liquid sample.
  • the test elements are typically based on an optical detectable reaction and evaluated visually or by optical instrumentation. Suitable filter elements are required to remove erythrocytes or other cellular or colored components from the liquid sample which would interfere with the optical readout of the test element.
  • filters comprising glass fiber fleece offer large filtration volumes per time due to their three-dimensional glass fiber network and may therefore be faster, may require less space and are hence considered advantageous over conventional filter membranes for separating blood cells from whole blood preparations.
  • glass fiber material and in particular material with a large surface area is prone to provide a large unspecific and undesired binding potential for sample components, for example for proteins.
  • unspecific binding of potential analytes to the filter surface may falsify the analysis result and hence be detrimental. Therefore, specifically protein-repellent coatings for filter materials are desired.
  • chemical modification of the surface of filter materials is used in the art to reduce or avoid unwanted binding of blood components and/or analytes such as proteins.
  • applying hydrophilic layers or coatings to filter materials including glass fiber material is proposed in the art to obtain protein-repellent filter materials suitable for biomedical applications such as blood filtration.
  • EP0457183 A1 suggests using a glass fiber comprising layer with an erythrocyte aggregating compound, wherein the glass fibers are coated with polyvinyl alcohol (PVA) or polyvinyl alcohol/polyvinyl acetate (PVAc) for separating red blood cells from plasma in whole blood preparations.
  • PVA polyvinyl alcohol
  • PVAc polyvinyl alcohol/polyvinyl acetate
  • the erythrocyte aggregating compound is applied to the coated glass fibers so that an additional erythrocyte aggregating layer is formed on the glass fibers.
  • the application of more than one coating to the glass fibers requires a laborious multistep process.
  • PVA layer typically adsorbs to the glass fiber surfaces, such that no permanent bonding to the surface of the glass fiber is established. Therefore, PVA or PVA/PVAc coatings typically wear off over time and may be prone to leaching.
  • EP1618940 A1 discloses a polymer coated glass fiber to obtain a glass fiber filter for blood filtration.
  • Preferred polymers for surface coating of the glass fibers are biocompatible polymers including acrylate polymers such as poly (alkoxy acrylate).
  • the coating is applied by immersing the acid cleaned glass fiber filter in a polymer solution.
  • the glass fiber filter may be prepared by laminating a plurality of sheets that may be approximately 0.2 to 3 mm thick.
  • JP2002350428 A disclose a fiber containing filter layer comprising glass fiber coated with butoxy group-attached propanol and/or acrylamide such as N-(butoxymethyl)acrylamide to suppress hemolysis when separating plasma or serum from whole blood.
  • acrylamide such as N-(butoxymethyl)acrylamide
  • Coated glass fiber filter paper may be produced by immersion in an aqueous solution of N-(butoxymethyl)acrylamide followed by drying at a temperature of 70°C.
  • the materials used for coating are often hydrophilic polymers. Due to their hydrophilicity, the coating materials do not make a stable contact with the underlying surface of the filter material and may be easily and quickly scrubbed off or leached out. In particular, there is no cross-linking of any these hydrophilic polymeric coating materials to the glass fiber fleece. Hence, the resulting non-cross-linked surface bound hydrophilic polymer coatings are easy to apply but offer limited stability and are prone to leaching.
  • More robust and longer lasting alternative coatings can be made by in situ polymerization or grafting from polymerization. This way polymeric coatings that are covalently bound and/or cross-linked to the underlying surface material can be obtained. These coatings possess enhanced stability and provide a long-lasting coating effect.
  • the underlying coating process is very complex and time consuming and cannot be easily applied to a three-dimensional structure including inner surfaces as that of glass fiber fleece.
  • the necessary and currently available polymerization techniques are often difficult to control at a production scale and in particular difficult to scale to high production numbers.
  • the cross-linking as performed by the present invention offers a simple but adaptable coating process. The cross-linking conditions can be adapted by the skilled artisan as desired.
  • cross-linking temperatures can be varied from about 60 °C to about 200 °C by selecting the appropriate cross-linker component.
  • the resulting structure is a durable three-dimensional polymeric network of the glass fiber fleece and the copolymer cross-linked thereto.
  • the present invention relates to a method for coating a glass fiber fleece comprising contacting the surface of a glass fiber fleece with a hydrophilic copolymer; and crosslinking the copolymer.
  • the present invention relates to a glass fiber filter comprising a glass fiber fleece, wherein the surface of the glass fiber fleece is coated with a hydrophilic copolymer; and to a device for biomedical filter applications comprising the same.
  • glass fiber fleece refers to a nonwoven fiber material.
  • the fibers may be of any type. They may in particular have a certain length, they may be filamentous or endless.
  • glass fiber fleece specifically refers to any type of nonwoven or undirected fiber structure.
  • the glass fiber fleece is typically characterized by a fibrous three-dimensional structure. More typically, the glass fiber fleece forms a three-dimensional network of fibers with irregular spacing. Due to their structure, glass fiber fleeces commonly have a large surface or large surface area. Specifically, their morphology is irregular.
  • Typical glass fiber fleece structures may include fibrous sheets, randomly dispersed fiber matrices, meshes, nonwoven fabrics and the like.
  • the glass fiber fleece is suitable for forming a filter material with a pore size suitable for separating cellular components out of liquid samples of bodily fluid; typically for separating blood cells such as erythrocytes from whole blood preparations.
  • Suitable pore sizes may be in the range of 1 ⁇ m to 10 ⁇ m; specifically in the range of 2 ⁇ m to 8 ⁇ m, or in the range of 3 ⁇ m to 6 ⁇ m.
  • Suitable commercial glass fiber filter products that may be used in line with the present invention are for example borosilicate glass fiber filter materials having an average pore size of 3 to 6 ⁇ m, such as GF/D type commercially available glass fiber fleece by Whatman or SureWick ® glass fiber fleeces available by Millipore Merck and/or similar products.
  • the glass fibers of the fleece used in the present invention have a fiber diameter in the nano- to micrometer range, e.g. between 1 nm to 1000 nm. Fiber diameter, pore size and/or fiber structure may be analyzed by techniques known in the art, for example by electron microscopic analysis.
  • Fleece fibers suitable in the method according to the present invention are made of glass or any type of known glass fiber material.
  • the glass fiber typically comprises soda-glass, low-alkali glass, borosilic acid glass, or quartz.
  • glass fiber filter and “glass fiber fleece filter” are used interchangeably herein.
  • the glass fiber fleece used in the present invention is typically used as a filter material; in particular for biomedical filter applications as specified elsewhere herein.
  • coating generally refers to a layer of material covering a surface of an object, in particular, the surface of a glass fiber fleece.
  • the term may in particular refer to a hydrophilic polymeric layer established by covalent bonding of a hydrophilic copolymer to a surface; more particularly, to the surface of a glass fiber fleece.
  • the coating is covalently bonded to the surface of the object, more particularly covalently bonded to the surface of a glass fiber fleece.
  • the coating according to the present invention specifically refers to a polymeric hydrogel coating.
  • said coating has a complex three-dimensional structure, typically being flexible.
  • the structure may particularly form a three-dimensional network of irregular morphology.
  • the term "hydrogel” refers to a polymer forming a complex hydrophilic polymeric network that has a large capacity for binding water. It is typically water insoluble but is permeable for water. Upon water binding, the volume of the polymer may increase, in other words, the hydrogel is capable of swelling in water.
  • Hydrogels are typically biocompatible and may exhibit biological tissue like mechanical properties.
  • the hydrogel typically comprises a hydrophilic copolymer and water.
  • a hydrogel forms upon crosslinking of the hydrophilic copolymer described elsewhere herein to the surface of a glass fiber fleece.
  • the crosslinking typically establishes intermolecular covalent bonds between the molecule chains of the copolymer and the glass fibers and more typically additional intramolecular covalent bonds between chains of the copolymer. These inter and intramolecular bonds typically generate the hydrophilic complex network forming the hydrogel coating.
  • the coating according to the invention may be applied by suitable techniques known in the art. These include for example, spraying, spin-coating, dip-coating, doctor blading, immersing or submerging the object to be coated into a coating solution. These techniques typically expose the surface to be coated to a coating formulation or a solution of the coating material.
  • the coating may be applied by submerging a glass fiber fleece into a solution of a hydrophilic copolymer.
  • Application of the coating by submerging into a solution of the copolymer appears advantageous, as it may access large parts, i.e. a large area, of the surface of the fleece material and may cover also inner surfaces that cannot be easily covered by other methods.
  • the terms "submerging” and "immersing” are used interchangeably herein. The application is described in further detail elsewhere herein.
  • the terms “have”, “comprise” or “include” or any arbitrary grammatical variations thereof are used in a non-exclusive way. Thus, these terms may both refer to a situation in which, besides the feature introduced by these terms, no further features are present in the entity described in this context and to a situation in which one or more further features are present.
  • the expressions “A has B”, “A comprises B” and “A includes B” may both refer to a situation in which, besides B, no other element is present in A (i.e. a situation in which A solely and exclusively consists of B) and to a situation in which, besides B, one or more further elements are present in entity A, such as element C, elements C and D or even further elements.
  • the terms "at least one”, “one or more” or similar expressions indicating that a feature or element may be present once or more than once typically will be used only once when introducing the respective feature or element.
  • the expressions “at least one” or “one or more” will not be repeated, non-withstanding the fact that the respective feature or element may be present once or more than once.
  • the method according to the invention comprises a step (a) of contacting the surface of a glass fiber fleece with a hydrophilic copolymer.
  • the glass fiber fleece material typically has a large surface or large surface area due to its three-dimensional structure formed by nonwoven undirected fibers. These fibers particularly form a large surface including inner surfaces that increase the overall surface area.
  • the term "surface of a glass fiber fleece” refers to the overall surface area and hence may reflect the sum of outer and inner surface area. More typically, the surface area of the glass fiber fleece may be estimated by determining the specific surface area. The specific surface area can be measured and determined by techniques known in the art.
  • the volume specific surface area can be calculated based on the occupied volume, the free volume and the volume of the fibers.
  • the coating solution advantageously can access the inner surface area in the step of submerging the glass fiber fleece into the solution of the hydrophilic copolymer.
  • the entire three dimensional structure of the glass fiber fleece is thought to be soaked by the copolymer solution.
  • the copolymeric coating can be crosslinked to the inner surface area of the glass fiber fleece establishing a stable covalent bonding.
  • the method of the present invention is advantageous as it provides a way of establishing a durable coating on the entire surface of a glass fiber fleece, including the inner surface area or at least parts thereof.
  • the method according to the present invention comprises step (a) of contacting the glass fiber with a solution of the copolymer; specifically with a low concentration of said copolymer. More specifically, step (a) of contacting comprises contacting the glass fiber with a solution containing 0.1 to 10 mg/mL of the copolymer; typically 0.2 to 2 mg/mL of the copolymer.
  • concentration is advantageous as although in the low range it is surprisingly already sufficient to establish a stable and durable coating with excellent protein repellent properties also on the inner surface.
  • the hydrophilic copolymer can be dissolved in an appropriate solvent to obtain a solution thereof.
  • a suitable solvent for the copolymer in line with the present invention may be a polar solvent, typically an aqueous buffer solution, ethanol or water.
  • the hydrophilic copolymer for use in the present invention in particular is water-soluble or at least partially water-soluble. It is more particularly capable of forming a hydrogel; still more particularly, it may form a hydrogel on the three-dimensional surface of a glass fiber fleece.
  • the hydrophilic copolymer specifically comprises at least first a monomer and at least a second monomer. More specifically, the hydrophilic copolymer comprises at least first a monomer comprising an acrylate or an acrylamide, even more specifically an N-alkyl acrylamide, and at least a second monomer comprising a crosslinker component. Still more specifically, the hydrophilic copolymer consists of a first a monomer comprising an acrylate or an acrylamide and a second monomer comprising a crosslinker component. In a particular copolymer of the invention, a typical crosslinker content ranges from 0.1 to 25 mol%, more typically the crosslinker content ranges from 0.5 to 10 mol%.
  • the specified ranges are advantageous due to the following effects: at higher crosslinker concentration, the water swellability of the forming polymeric network is strongly attenuated due to the hydrophobic nature of the crosslinker units and at very low concentrations, the resulting hydrogels become mechanically fragile.
  • the first monomer is or consists of an acrylate or an acrylamide.
  • the acrylamide is selected from the group consisting of acrylamide, N -methyl acrylamide, N,N -dimethyl acrylamide, N -ethyl acrylamide, N -propyl acrylamide, N -butyl acrylamide, and N,N -diethyl acrylamide; and the acrylate is selected from 2-hydroxymethylacrylate and 2-hydroxyacrylate.
  • the second monomer is or consists of a crosslinker component.
  • cross-linker typically relates to a chemical component that upon activation is capable of forming a reactive intermediate such as a radical. More typically, the cross-linker can be activated thermally or by photo-activation.
  • activation typically relates to a treatment resulting in the formation of a reactive intermediate. Hence, thermal activation refers to heat treatment while photo-activation refers to treatment with UV irradiation. Both treatments lead to the formation of the reactive intermediate.
  • the crosslinker component is a crosslinker selected from the group consisting of azides and diazo group containing crosslinkers.
  • a typical azid crosslinker useful in the present invention is a sulfonyl azide such as 4-styrenesulfonyl azide or 4-propylbenzenesul-fonyl azide.
  • the crosslinker may be a diazo group containing crosslinker selected from the group consisting of: 2-(2-diazo-2-phenylacetoxy)ethylmethacrylate, or 1-(4-(methacryloyloxy)butyl)-3-methyl-2-diazomalonate.
  • the reactive intermediate that is formed from said crosslinker is typically a carbene or a nitrene radical.
  • the hydrophilic copolymer may be represented by the following formula, formula A: wherein R 1 and R 2 are independently from each other selected from H, CH 3 , C 2 H 5 , C 3 H 7 .
  • Rc respresents the crosslinker component.
  • Rc may typically be selected from:
  • n and m represent a number between 1 and 2000. More typically, n is between 10 and 1000 and/or m is between 5 and 100.
  • the copolymer is a statistical copolymer. In other words, specifically the monomers are statistically distributed in the copolymer. More specifically, n has a number that is larger than m. Still more specifically, the number of n is at least two times the number of m: even more specifically the number of n is at least three, at least four, at least five, at least ten times the number of m. In a typical copolymer according to the invention, n and m represent a number between 1 and 2000, typically n is between 10 and 1000 and/or m is between 5 and 100.
  • R 3 is typically an azide or diazo group containing residue; more typically R 3 is selected from:
  • R 4 is typically selected from H, OH, F, Cl, CH 3 , C 2 H 5 , C 3 H 7 ; more typically, R 4 is H or CH 3 , even more typically H.
  • n and m represent a number between 1 and 2000. More typically n is between 10 and 1000 and/or m is between 5 and 100.
  • hydrophilic copolymer according to the present invention may be represented by formula I:
  • R 1 , R 2 and R 3 are as defined above.
  • hydrophilic copolymer may alternatively, be represented by the following formula, formula II:
  • R 1 and R 2 are, as in formula I, typically independently from each other selected from H, CH 3 , C 2 H 5 , C 3 H 7 .
  • the numbers for n and m are as in formula I.
  • n and m represent a number between 1 and 2000. More typically n is between 10 and 1000 and/or m is between 5 and 100.
  • crosslinker component can be synthesized as known in the art and exemplified elsewhere herein.
  • the copolymer can be obtained via conventional free-radical copolymerization with co-monomers that typically form water soluble polymers. More typically, the copolymer forms a hydrogel.
  • the copolymer can be obtained via free-radical copolymerization using as co-monomers, the at least first and at least second monomer as specified elsewhere herein.
  • common radical initiators typically 2,2'-azobis(2-methylpropionitril) (AIBN) or the like.
  • the hydrophilic copolymer comprises at least a content of 2.5 mol% of crosslinker component, typically at least 5 mol% of cross-linker component.
  • the content of crosslinker within the copolymer can be determined by NMR analysis, e.g. 1 H-NMR analysis. The respective means and methods are well known in the art. Further details are described in the example section below.
  • Typical examples for a copolymer according to the present invention are represented by the following structural formulas:
  • the glass fiber fleece is contacted with the hydrophilic copolymer typically as a first step in the coating process.
  • the contacting step may refer to any way of applying or coating the copolymer solution onto the glass fiber surface including spin or dip coating, spraying, submerging or doctor blading.
  • the contacting may more specifically refer to submerging the glass fiber fleece in the solution of the copolymer.
  • the submerging is performed for a time suitable for wetting or soaking the entire surface area of the glass fiber fleece. More typically, the submerging is performed for at least 30 min, still more typically for at least 45 min, even more typically for at least 60 min.
  • Submerging may take place for a up to 2 h.
  • the glass fiber fleece may typically be constantly shaken to ensure complete wetting of the entire surface area of the glass fiber fleece.
  • Submerging combined with shaking has the advantageous effect that the contact area between the hydrophilic copolymer solution and the surface of the glass fiber fleece may be maximized. Thereby, ideally an essentially completely soaked glass fiber fleece can be obtained.
  • the method may comprise a step of removing residual solvent that may arise from the hydrophilic copolymer solution.
  • the glass fiber fleece is removed from the copolymer solution and the solvent is evaporated at a temperature of 50 °C or above.
  • the solvent may be removed at a temperature of 60 °C or above. More specifically, the temperature shall not exceed 100 °C.
  • a temperature range of between 50 °C and 100 °C is specifically suitable as the solvent may be completely evaporated while the crosslinking reaction will not be started.
  • the method according to the invention comprises a step of crosslinking the copolymer.
  • the crosslinking step establishes a covalent bond between the copolymer and the glass fiber fleece.
  • crosslinking generally refers to a chemical reaction establishing a link or chemical bond between two different molecules or molecule chains, in particular polymer chains.
  • cross-linking in particular refers to establishing a chemical bond between the glass fiber fleece and the hydrophilic copolymer.
  • the chemical bond established by the crosslinking is typically a covalent bond.
  • a covalent bond is advantageous as it establishes a stable, durable and long lasting coating of the copolymer on the surface of the glass fiber fleece.
  • the crosslinking step of the method of the present invention typically comprises a C-H insertion mechanism; specifically the crosslinking occurs by a C-H insertion mechanism. This is also referred to as C-H insertion reaction and specified elsewhere herein in more detail.
  • the crosslinking in the method of the present invention in particular refers to establishing a surface-attached hydrophilic copolymer network on the surface of the glass fiber fleece.
  • a copolymeric network is created on the three-dimensional structure of the glass fiber fleece surface that even more increases the overall inner surface area.
  • the hydrophilic copolymeric coating may also be referred to as a hydrogel or hydrogel coating.
  • the described crosslinking step establishes the surface-attached polymer network. More typically, the crosslinking establishes a covalent bond between the copolymer and the glass fiber fleece thereby creating a surface-attached polymer network on the glass fiber surface.
  • the resulting coated glass fiber fleece surprisingly has excellent protein repellent properties in particular in blood filter applications.
  • the copolymer is covalently bonded to the glass fiber by a C-H insertion reaction or C-H insertion mechanism.
  • the C-H insertion reaction and methodology for stable surface-attached polymeric coatings has recently been established in the art and is for example reviewed in Prucker et al. (Biointerphases, Vol. 13, No. 1, Jan/Feb 2018 ) and Kotrade and Rühe (Angew. Chem. Int. Ed. 2017, 56, 14405 -14410 ).
  • the reaction relies on the incorporation of groups with latent reactivity, herein designated as a crosslinker component, as pendant co-monomers into the copolymer to be deposited.
  • the respective copolymers are, in a first step, applied to the surface of an object to be coated using standard coating techniques such as spin or dip coating, spraying, or doctor blading.
  • a reactive intermediate forms upon thermal or photo-activation from the crosslinker, such as a nitrene or a carbene.
  • the reactive intermediate can insert into a C-H bond of the surface material, establishing a covalent bond between the copolymer and the surface of the object.
  • the methodology has been successfully used only for coating flat surfaces but not to three-dimensional structures such as the surface of glass fiber fleece. It was generally assumed in the art, that applying a polymeric coating to a three-dimensional structure such as a glass fiber fleece would clog or reduce the free space in the three-dimensional network and hence would lead to a reduction in the filter capacities of the coated material. The present inventors surprisingly found that contrary to the general assumption, the filter capacities were excellent and the protein repellency was superior in the resulting copolymer coated glass fiber fleece material.
  • the crosslinking in step (b) typically comprises heating the copolymer contacted with the glass fiber to at least 40 °C, specifically to at least 50 °C; more specifically to a temperature between 50 °C and 200 °C.
  • the crosslinker may typically be activated by thermal activation, i.e. by applying thermal energy or heat to the copolymer.
  • the application of thermal energy is in particular performed in an oven set to an appropriate temperature.
  • other routes of heating the copolymer may be envisaged such as pressure application.
  • the crosslinker may be photo-activated such as by UV- irradiation.
  • thermal activation is regarded as being advantageous for coating of surfaces with a three-dimensional structure such as glass fiber fleece since it may also reach the inner surface area and allow for a cross-linking reaction there.
  • the heating step i.e. the step for thermal activation, is typically performed for at least 15 minutes, typically at least 20 min, more typically for at least 20 minutes up to 2 hours; even more typically between 20 min and 1 h.
  • the time required for thermal activation may vary depending on the temperature applied. At a lower temperature, such as 120 °C, 1h of activation time may be needed for sufficient crosslinking, while at a temperature of 160 °C 30 min may be already sufficient for achieving an efficient crosslinking.
  • the method of the invention may comprise any or all of the following additional steps:
  • One typical method in line with the present invention may have the following steps:
  • step (a) the contacting comprises submerging the glass fiber fleece in a solution of the hydrophilic copolymer in a suitable solvent; the submerging may optionally be accompanied by constantly shaking the submerged glass fiber fleece; further optionally the submerging may be followed by evaporating the solvent.
  • the method may typically involve a step of washing and/or drying the coated glass fiber fleece typically after the crosslinking (b) is performed; and prior to obtaining the coated glass fiber fleece (step (c)).
  • the glass fiber fleece coated in line with the present invention is particularly suitable as filter material in biomedical filter applications, typically blood filtration; more typically removal of blood cells, in particular erythrocytes, from whole blood preparations.
  • the present invention relates to a glass fiber filter, comprising a glass fiber fleece, wherein the surface of the glass fiber fleece is coated with a hydrophilic copolymer network.
  • the glass fiber filter according to the present invention is coated is coated with a hydrophilic copolymer or copolymer network as specified elsewhere herein; specifically, the coating comprises a covalent bonding between the copolymer and the glass fiber.
  • the present invention contemplates a device for biomedical filter applications, typically blood filtration, comprising a glass fiber filter as specified elsewhere herein.
  • the present invention contemplates a method for separating plasma from blood, comprising filtering the blood with a glass fiber filter or device according to the invention.
  • the present invention further relates to the use of a hydrophilic copolymer for coating a glass fiber fleece.
  • the diazomalonic ester monomer (MAz) was obtained following the reaction pathway as known in the art and described e.g. in Kotrade and Rühe (Angew. Chem. Int. Ed. 2017, 56, 14405 -14410 ).
  • methyl malonyl chloride is transformed into 4-hydroxybutyl methyl malonate, followed by esterification with methacryloyl chloride and subsequent functionalization of the C-H acidic malonate group through a Regitz diazo-transfer reaction.
  • an azide was used to transfer a diazo group to the target molecule to yield the polymerizable diazomalonic ester (MAz).
  • a dried Schlenk tube was prepared.
  • the monomers MAz and DMMA were added to the tube and dissolved in DMF.
  • the initiator AIBN was also dissolved in DMF and added to the tube. Dissolved gases were removed by repeated cycles (6 times) of freezing the solution by liquid nitrogen, and thawing under vacuum.
  • the solution was polymerized under vacuum application overnight at 60 °C in a water bath. Thereafter, the copolymer was precipitated in 300 ml diethylether; resolved in chloroform and again precipitated in 300 ml diethylether. Drying was performed overnight by application of a high vacuum. The copolymer was obtained as a white solid substance.
  • the obtained copolymer was analyzed to determine the crosslinker content, and other molecular characteristics
  • the synthesis was analogous to example 1 above.
  • the main monomer was 2-hydroxyethylmethacrylate (HEMA).
  • HEMA 2-hydroxyethylmethacrylate
  • the glass fiber fleece as submerged in a solution of the copolymer of 2 mg/ml.
  • a crosslinker content of 7.5 mol% was determined by 1 H-NMR.
  • p(HEMA-MAz) For synthesizing p(HEMA-MAz) a dried Schlenk tube was prepared. The monomers MAz and HEMA were added to the tube and dissolved in DMF. The initiator AIBN was also dissolved in DMF and added to the tube. Dissolved gases were removed by repeated cycles (4 times) of freezing the solution by liquid nitrogen, and thawing under vacuum.
  • the solution was polymerized under vacuum application overnight at 60 °C in a water bath. Thereafter, the copolymer was precipitated in 300 ml diethylether; resolved in chloroform and again precipitated in 300 ml diethylether. Drying was performed overnight by application of a high vacuum. The copolymer was obtained as a white solid substance.
  • the crosslinker group was 2-(2-diazo-2-phenylacetoxy)ethyl methacrylate (PEDAZ).
  • PEDAZ 2-(2-diazo-2-phenylacetoxy)ethyl methacrylate
  • p(DMMA-PEDAZ) For synthesizing p(DMMA-PEDAZ) a dried Schlenk tube was prepared. The monomers PEDAZ and DMMA were added to the tube and dissolved in DMF. The initiator AMDVN was also dissolved in DMF and added to the tube. Dissolved gases were removed by repeated cycles (4 times) of freezing the solution by liquid nitrogen, and thawing under vacuum.
  • the solution was polymerized under vacuum application overnight at 30 °C in a water bath. Thereafter, the copolymer was precipitated in 300 ml diethylether; resolved in chloroform and again precipitated in 300 ml diethylether. Drying was performed overnight by application of a high vacuum. The copolymer was obtained as a white solid substance.
  • the obtained copolymer was analyzed to determine the crosslinker content, and other molecular characteristics
  • Example 4 Coating a glass fiber fleece
  • the glass fiber fleece was submerged in a solution of the copolymer in ethanol at a copolymer concentration of 0.1 mg/ml for 1 h under constant shaking. It is thought that the shaking ensures complete soaking of the copolymer solution into the fiber structure of the glass fiber fleece. Thereafter, the solvent was evaporated at a minimum temperature of 60 °C for at least 3 h.
  • the glass fiber fleece was washed for 2h in ethanol to remove non-cross-linked copolymer from the glass fiber fleece. After washing the coated glass fiber fleece was dried to evaporate the solvent at a minimum temperature of 60 °C for at least 3 h.
  • Example 5 Experimental analysis of the coated glass fiber fleece - troponin T recovery
  • the concentration of troponin T was reduced to about 30 -40 % for cardiac fleece or uncoated fleece.
  • the p(DMMA-MAz)_coated glass fiber fleece according to the invention retained 85-90 % of the original troponin T concentration.
  • the concentration of troponin T was reduced to about 50 -60 % for cardiac fleece.
  • the p(HEMA-MAz) coated glass fiber fleece according to the invention retained 80 % of the original troponin T concentration (see Fig. 2 ).
  • the concentration of troponin T was reduced to about 55 -60 % for cardiac fleece.
  • the p(DMMA-PEDAZ) coated glass fiber fleece according to the invention retained about 90 % of the original troponin T concentration (see Fig. 3 ).
  • Example 6 Experimental analysis of the coated glass fiber fleece -Lateral flow assay The coating of glass fiber fleece material was prepared as described in examples 1 and 4 above (p(DMMA-MAz) with the only difference that the crosslinking was performed at the above described temperature of 160 °C for 30 min or at a reduced temperature of 120 °C for 60 min.
  • the different fleece materials were analyzed in a lateral flow assay (LFA) for troponin T.
  • LFA lateral flow assay
  • Blood samples of known troponin T concentration were applied to the LFA and quantitatively analyzed in a cobas h232 device (Roche Diagnostics).
  • a low remission signal corresponds to a high single intensity.
  • Both of the glass fiber fleece materials coated in line with the invention showed a better signal intensity than the commercially available cardiac fleece (see Fig. 4 ).
  • the coating of glass fiber fleece material was prepared as described in examples 1 and 4 above (p(DMMA-MAz) with the only difference that the coating of the glass fiber fleece material was performed using different p(DMMA-MAz) concentrations, 0.1, 1 or 10 mg/ml.
  • the glass fiber fleece material was assayed for troponin T recovery as described in example 5 above. The results are depicted in Fig. 5 .
  • Example 8 Troponin T recovery compared to BSA coated glass fiber fleece
  • the glass fiber fleece material was assayed for troponin T recovery as described in example 5 above. The results are depicted in Fig. 6 .
  • the density of the glass fiber fleece material was estimated by calculating the volume and determining the weight of a given piece of glass fiber material. The density was estimated to be around 0.13 g/cm 3 . This represents a density in line with the recommendation for a glass fiber fleece for whole blood separation. Based on the density of glass of 2.5 g/cm 3 a free volume of 95 % was calculated.
  • the fiber structure of the glass fiber fleece was undirected and there were smaller and larger areas of free space between individual fibers.
  • the diameter of the fiber was non-uniform but varied in the range of below 1 ⁇ m to more than 5 ⁇ m.
  • V F ⁇ ⁇ l ⁇ d / 2 2 ; resulting in V F ⁇ 3 ⁇ 10 -9 cm 3 .
  • V Ges 20 V F ; resulting in V Ges ⁇ 6 ⁇ 10 -8 cm 3 .
  • O spez. O F /V Ges ; resulting in O spez. ⁇ 1000 cm 2 /cm 3 .
  • the glass fiber fleece has a large surface area with an irregular morphology.
  • Such structures are expected to lead to undesired structural effects during coating and to result in unwanted adsorption of proteins; in particular blood proteins during whole blood separation.

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EP23212012.1A 2023-11-24 2023-11-24 Procédé de revêtement d'un non-tissé de fibres de verre, filtre à fibres de verre revêtu et ses utilisations Withdrawn EP4559565A1 (fr)

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PCT/EP2024/083324 WO2025109187A1 (fr) 2023-11-24 2024-11-22 Procédé de revêtement d'une nappe de fibres de verre, filtre à fibres de verre revêtu et ses utilisations

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0457183A1 (fr) 1990-05-15 1991-11-21 Roche Diagnostics GmbH Appareil et son utilisation pour la séparation de plasma du sang
JP2002350428A (ja) 2001-05-28 2002-12-04 Sanko Junyaku Kk 全血からの血漿又は血清分離方法及び器具
EP1618940A1 (fr) 2004-07-23 2006-01-25 Fuji Photo Film Co., Ltd. Filter à fibres de verre pour dispositif de filtration sanguine et élèment d'analyse sanguine
CN102614556A (zh) * 2012-04-19 2012-08-01 南京红十字血液中心 一种高效滤除白细胞的组合滤膜及其制法和白细胞过滤器
US20140170918A1 (en) * 2012-12-14 2014-06-19 Hollingsworth & Vose Company Durable fiber webs
US20160268566A1 (en) * 2015-03-09 2016-09-15 Johns Manville Acid resistant glass mats that include binders with hydrophilic agents
WO2023069566A1 (fr) * 2021-10-20 2023-04-27 Streck, Inc. Procédé de revêtement par pulvérisation d'un hydrogel fixé en surface

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0457183A1 (fr) 1990-05-15 1991-11-21 Roche Diagnostics GmbH Appareil et son utilisation pour la séparation de plasma du sang
JP2002350428A (ja) 2001-05-28 2002-12-04 Sanko Junyaku Kk 全血からの血漿又は血清分離方法及び器具
EP1618940A1 (fr) 2004-07-23 2006-01-25 Fuji Photo Film Co., Ltd. Filter à fibres de verre pour dispositif de filtration sanguine et élèment d'analyse sanguine
CN102614556A (zh) * 2012-04-19 2012-08-01 南京红十字血液中心 一种高效滤除白细胞的组合滤膜及其制法和白细胞过滤器
US20140170918A1 (en) * 2012-12-14 2014-06-19 Hollingsworth & Vose Company Durable fiber webs
US20160268566A1 (en) * 2015-03-09 2016-09-15 Johns Manville Acid resistant glass mats that include binders with hydrophilic agents
WO2023069566A1 (fr) * 2021-10-20 2023-04-27 Streck, Inc. Procédé de revêtement par pulvérisation d'un hydrogel fixé en surface

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KOTRADERIIHE: "Malonic Acid Diazoesters for C-H Insertion Crosslinking (CHic) Reactions: A Versatile Method for the Generation of Tailor-Made Surfaces", ANGEW. CHEM. INT., vol. 56, 2017, pages 14405 - 14410, XP055560203, DOI: 10.1002/anie.201704486
KOTRADERUHE, ANGEW. CHEM. INT. ED., vol. 56, 2017, pages 14405 - 14410
PRUCKER ET AL.: "Surface-attached hydrogel coatings via C,H-insertion crosslinking for biomedical and bioanalytical applications (Review", BIOINTERPHASES, vol. 13, no. 1, January 2018 (2018-01-01)

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